Newsletter Issue 03 May-Jun 2008

Copper-Catalyzed Domino Annulation Approaches to the Synthesis of Benzoxazoles under Microwave-Accelerated and Conventional Thermal Conditions

Benzoxazoles are widespread among medicinal chemistry targets. The usual synthesis of benzoxazoles uses as raw materials a 2-aminophenol and an acid or aldehyde. Obviously this narrow the scope of starting materials available for the synthesis of benzoxazoles, and methods using a new pool of compounds are always welcome. The group of Batey (Toronto, Canada) had published in 2006 a first work in this direction, and they have presented now a paper with two domino approaches for the synthesis of Benzoxazoles. The first approach uses 1,2-dihalobenzenes and primary amides, with a first intermolecular copper-catalyzed C-N cross-coupling, followed by intramolecular copper-catalyzed C-O cross-coupling. However, this approach is limited both by the availability of 1,2-dihaloarenes and regioselectivity problems. The second approach, and clearly the winning one, starts from 2-haloanilines and acyl chlorides, building the oxazole ring with an intermolecular N-acylation, followed by intramolecular copper-catalyzed C-O cross-coupling using CuI, Cs2CO3 and 1,10-phenantroline in DME at reflux. There is plenty of commercial 2-haloanilines and acyl chlorides, which makes this approach much more interesting. Though the original method involves extended times, a microwave-assisted methodology is also developed, with reaction times of 15 minutes and good yields. This protocol is used for the automated preparation of a library of 24 benzoxazoles with an average yield of 72%.

J. Org. Chem., 73 (9), 3452–3459, 2008. See: 10.1021/jo702145d

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